Chlorhexidine-containing medical devices

ABSTRACT

The present invention relates to polymeric medical articles comprising the anti-infective agents chlorhexidine and triclosan. It is based, at least in part, on the discovery that the synergistic relationship between these compounds permits the use of relatively low levels of both agents, and on the discovery that effective antimicrobial activity may be achieved when these compounds are comprised in either hydrophilic or hydrophobic polymers. It is also based on the discovery that chlorhexidine free base and triclosan, used together, are incorporated into polymeric medical articles more efficiently. Medical articles prepared according to the invention offer the advantage of preventing or inhibiting infection while avoiding undesirably high release of anti-infective agent, for example into the bloodstream of a subject.

REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. patent application Ser. No.09/618,432 filed Jul. 18, 2000 (issued as U.S. Pat. No. 6,626,873),which is a continuation of U.S. patent application Ser. No. 09/101,129,filed Jun. 30, 1998 (issued as U.S. Pat. No. 6,106,505), which is anational phase application pursuant to 35 U.S.C. §371 of PCT/US96/20932,filed Dec. 23, 1996, which is a continuation-in-part of U.S. patentapplication Ser. No. 08/583,239, filed Jan. 5, 1996, issued as U.S. Pat.No. 5,772,640.

BACKGROUND OF THE INVENTION

The present invention relates to medical devices comprising synergisticcombinations of triclosan and chlorhexidine.

Whenever a medical device comes in contact with a patient, a risk ofinfection is created. Thus, a contaminated examination glove, tonguedepressor, or stethoscope could transmit infection. The risk ofinfection dramatically increases for invasive medical devices, such asintravenous catheters, arterial grafts, intrathecal or intracerebralshunts and prosthetic devices, which not only are, themselves, inintimate contact with body tissues and fluids, but also create a portalof entry for pathogens.

A number of methods for reducing the risk of infection have beendeveloped which incorporate anti-infective agents into medical devices,none of which have been clinically proven to be completely satisfactory.Such devices desirably provide effective levels of anti-infective agentduring the entire period that the device is being used. This sustainedrelease may be problematic to achieve, in that a mechanism fordispersing anti-infective agent over a prolonged period of time may berequired, and the incorporation of sufficient amounts of anti-infectiveagent may adversely affect the surface characteristics of the device.The difficulties encountered in providing effective anti-microbialprotection increase with the development of drug-resistant pathogens.

One potential solution to these problems is the use of a synergisticcombination of anti-infective agents that requires relatively lowconcentrations of individual anti-infective agents which may havediffering patterns of bioavailability.

Two well known anti-infective agents are chlorhexidine and triclosan.The following patents and patent application relate to the use ofchlorhexidine and/or triclosan in medical devices.

U.S. Pat. No. 4,723,950 by Lee relates to a microbicidal tube which maybe incorporated into the outlet tube of a urine drainage bag. Themicrobicidal tube is manufactured from polymeric materials capable ofabsorbing and releasing anti-microbial substances in a controllable,sustained, time-release mechanism, activated upon contact with dropletsof urine, thereby preventing the retrograde migration of infectiousorganisms into the drainage bag. The microbicidal tube may be producedby one of three processes: (1) a porous material, such as polypropylene,is impregnated with at least one microbicidal agent, and then coatedwith a hydrophilic polymer which swells upon contact with urine, causingthe leaching-out of the microbicidal agent; (2) a porous material, suchas high density polyethylene, is impregnated with a hydrophilic polymerand at least one microbicidal agent; and (3) a polymer, such assilicone, is compounded and co-extruded with at least one microbicidalagent, and then coated with a hydrophilic polymer. A broad range ofmicrobicidal agents are disclosed, including chlorhexidine andtriclosan, and combinations thereof. The purpose of Lee's device is toallow the leaching out of microbicidal agents into urine contained inthe drainage bag; similar leaching of microbicidal agents into thebloodstream of a patient may be undesirable.

U.S. Pat. No. 5,091,442 by Milner relates to tubular articles, such ascondoms and catheters, which are rendered antimicrobially effective bythe incorporation of a non-ionic sparingly soluble antimicrobial agent,such as triclosan. The tubular articles are made of materials whichinclude natural rubber, polyvinyl chloride and polyurethane.Antimicrobial agent may be distributed throughout the article, or in acoating thereon. A condom prepared from natural rubber latex containing1% by weight of triclosan, then dipped in an aqueous solution ofchlorhexidine, is disclosed. U.S. Pat. Nos. 5,180,605 and 5,261,421,both by Milner, relate to similar technology applied to gloves.

U.S. Pat. Nos. 5,033,488 and 5,209,251, both by Curtis et al., relate todental floss prepared from expanded polytetrafluoroethylene (PTFE) andcoated with microcrystalline wax. Antimicrobial agents such aschlorhexidine or triclosan may be incorporated into the coated floss.

U.S. Pat. No. 5,200,194 by Edgren et al. relates to an oral osmoticdevice comprising a thin semipermeable membrane wall surrounding acompartment housing a “beneficial agent” (that is at least somewhatsoluble in saliva) and a fibrous support material composed ofhydrophilic water-insoluble fibers. The patent lists a wide variety of“beneficial agents” which may be incorporated into the oral osmoticdevice, including chlorhexidine and triclosan.

U.S. Pat. No. 5,019,096 by Fox, Jr. et al. relates toinfection-resistant medical devices comprising a synergistic combinationof a silver salt (such as silver sulfadiazine) and chlorhexidine.

International Patent Application No. PCT/GB92/01481, Publication No. WO93/02717, relates to an adhesive product comprising residues of aco-polymerizable emulsifier comprising a medicament, which may bepovidone iodine, triclosan, or chlorhexidine.

In contrast to the present invention, none of the above-cited referencesteach medical articles comprising synergistic combinations ofchlorhexidine and triclosan which utilize relatively low levels of theseagents.

SUMMARY OF THE INVENTION

The present invention relates to polymeric medical articles comprisingthe anti-infective agents chlorhexidine and triclosan. It is based, atleast in part, on the discovery that the synergistic relationshipbetween these compounds permits the use of relatively low levels of bothagents, and on the discovery that effective antimicrobial activity maybe achieved when these compounds are comprised in either hydrophilic orhydrophobic polymers. It is also based on the discovery thatchlorhexidine free base and triclosan, used together, are incorporatedinto polymeric medical articles more efficiently. Medical articlesprepared according to the invention offer the advantage of preventing orinhibiting infection while avoiding undesirably high release ofanti-infective agent, for example into the bloodstream of a subject.

DETAILED DESCRIPTION OF THE INVENTION

The present invention relates to medical articles comprising synergisticcombinations of chlorhexidine and triclosan.

Chlorhexidine may be provided by way of any form, salt or derivativethereof, including but not limited to chlorhexidine free base andchlorhexidine salts such as chlorhexidine diphosphanilate, chlorhexidinedigluconate, chlorhexidine diacetate, chlorhexidine dihydrochloride,chlorhexidine dichloride, chlorhexidine dihydroiodide, chlorhexidinediperchlorate, chlorhexidine dinitrate, chlorhexidine sulfate,chlorhexidine sulfite, chlorhexidine thiosulfate, chlorhexidine di-acidphosphate, chlorhexidine difluorophosphate, chlorhexidine diformate,chlorhexidine dipropionate, chlorhexidine di-iodobutyrate, chlorhexidinedi-n-valerate, chlorhexidine dicaproate, chlorhexidine malonate,chlorhexidine succinate, chlorhexidine malate, chlorhexidine tartrate,chlorhexidine dimonoglycolate, chlorhexidine monodiglycolate,chlorhexidine dilactate, chlorhexidine di-α-hydroxyisobutyrate,chlorhexidine diglucoheptonate, chlorhexidine di-isothionate,chlorhexidine dibenzoate, chlorhexidine dicinnamate, chlorhexidinedimandelate, chlorhexidine di-isophthalate, chlorhexidinedi-2-hydroxynaphthoate, and chlorhexidine embonate. The term“chlorhexidine”, as used herein, may refer to any of such forms,derivatives, or salts, unless specified otherwise. Chlorhexidine saltsmay be solubilized using polyethylene glycol or propylene glycol, orother solvents known in the art.

The term triclosan refers to a compound also known as2,4,4′-trichloro-2′-hydroxydiphenyl ether.

Medical articles that may be treated according to the invention areeither fabricated from or coated or treated with biomedical polymer andinclude, but are not limited to, catheters including urinary cathetersand vascular catheters (e.g., peripheral and central vascularcatheters), wound drainage tubes, arterial grafts, soft tissue patches,gloves, shunts, stents, tracheal catheters, wound dressings, sutures,guide wires and prosthetic devices (e.g., heart valves and LVADs).Vascular catheters which may be prepared according to the presentinvention include, but are not limited to, single and multiple lumencentral venous catheters, peripherally inserted central venouscatheters, emergency infusion catheters, percutaneous sheath introducersystems and thermodilution catheters, including the hubs and ports ofsuch vascular catheters.

The present invention may be further applied to medical articles thathave been prepared according to U.S. Pat. No. 5,019,096 by Fox, Jr. etal.

The present invention provides, in various alternative non-limitingembodiments, for: (1) compositions which provide a local concentrationof chlorhexidine of between 100 and 2000 μg/ml and a local concentrationof triclosan of between 250 and 2000 μg/ml; (2) treatment solutions of apolymer comprising between 1 and 5 percent, and preferably between 1.5and 2.25 percent, of chlorhexidine; and between 0.5 and 5 percent, andpreferably between 0.5 and 2 percent, of triclosan, wherein a medicalarticle may be dipped or soaked in the polymer solution; (3) medicalarticles treated with a treatment solution as set forth in (2) above,and articles physically equivalent thereto (that is to say, articlesprepared by a different method but having essentially the same elementsin the same proportions); (4) treatment solutions of a polymercomprising between 1 and 5 percent, and preferably between 1.5 and 2.25percent, of chlorhexidine; between 0.5 and 5 percent, and preferablybetween 0.5 and 2 percent, of triclosan; and between 0.5 and 1 percent(preferably 0.75 percent) of silver sulfadiazine, wherein a medicalarticle may be dipped or soaked in the polymer solution; and (5) medicalarticles treated with a treatment solution set forth in (4) above, andarticles physically equivalent thereto (that is to say, articlesprepared by a different method but having essentially the same elementsin the same proportions). Percentages recited herein refer to percent byweight, except as indicated otherwise.

In preferred embodiments, the ratio, by weight, of the total amount ofanti-infective agent to polymer in the treatment solution is less than1.5.

In one particular non-limiting embodiment, the present inventionprovides for a hydrophilic polymeric medical article (i.e., a medicalarticle fabricated from a hydrophilic polymer) treated by dipping orsoaking the article in a treatment solution of a hydrophilic polymercomprising chlorhexidine and triclosan wherein the chlorhexidine andtriclosan are present in amounts such that their combination, in thetreated article, has effective antimicrobial activity. The terms“treat”, “treated”, etc., as used herein, refer to coating,impregnating, or coating and impregnating a medical article withpolymer/anti-infective agent. The term “hydrophilic polymer”, as usedherein, refers to polymers which have a water absorption greater than0.6 percent by weight (and, in preferred embodiments, less than 2percent by weight; as measured by a 24 hour immersion in distilledwater, as described in ASTM Designation D570-81) including, but notlimited to biomedical polyurethanes (e.g., ether-based polyurethanes andester-based polyurethanes, as set forth in Baker, 1987, in ControlledRelease of Biologically Active Agents, John Wiley and Sons, pp. 175-177and Lelah and Cooper, 1986, Polyurethanes in Medicine, CRC Press, Inc.,Fla. pp. 57-67; polyurethanes comprising substantially aliphaticbackbones such as Tecoflex™ 93A; polyurethanes comprising substantiallyaromatic backbones such as Tecothane™; and Pellethane™), polylacticacid, polyglycolic acid, natural rubber latex, and gauze orwater-absorbent fabric, including cotton gauze and silk suture material.In a specific, non-limiting embodiment, the hydrophilic medical articleis a polyurethane catheter which has been treated with (i.e., dipped orsoaked in) a treatment solution comprising (i) between about 1 and 10percent, preferably between about 2 and 6 percent, and more preferablyabout 3 percent, of a biomedical polyurethane; (ii) between 1 and 5percent, and preferably between 1.5 and 2.25 percent, of chlorhexidine;and (iii) between 0.5 and 5 percent, and preferably between 0.5 and 2percent, of triclosan. In related non-limiting embodiments of theinvention, the treatment solution may further comprise silversulfadiazine, preferably in a concentration of between 0.5 and 1 percent(more preferably 0.75 percent). Section 6, below, presents workingexamples of embodiments set forth in this paragraph.

In another particular non-limiting embodiment, the present inventionprovides for a hydrophilic polymeric medical article treated by dippingor soaking the article in a treatment solution of a hydrophobic polymercomprising chlorhexidine and triclosan, wherein the chlorhexidine andtriclosan are present in amounts such that their combination, in thetreated article, has effective antimicrobial activity. The term“hydrophobic polymer”, as used herein, refers to a polymer which has awater absorption of less than 0.6 percent and includes, but is notlimited to, silicone polymers such as biomedical silicones (e.g.,Silastic Type A) or elastomers (e.g., as set forth in Baker, 1987, inControlled Release of Biologically Active Agents, John Wiley and Sons,pp. 156-162), Dacron, polytetrafluoroethylene (PTFE, also “Teflon”),polyvinyl chloride, cellulose acetate, polycarbonate, and copolymerssuch as silicone-polyurethane copolymers (e.g., PTUE 203 and PTUE 205polyurethane-silicone interpenetrating polymer). In a specific,non-limiting embodiment, the medical article is a polyurethane catheterwhich has been dipped or soaked in a treatment solution comprising (i)between about 1 and 10 percent, preferably between about 2 and 6percent, and more preferably about 3 percent, of a polyurethane-siliconecopolymer; (ii) between 1 and 5 percent, and preferably between 1.5 and2.25 percent, of chlorhexidine; and (iii) between 0.5 and 5 percent, andpreferably between 0.5 and 2 percent, of triclosan. In relatednon-limiting embodiments of the invention, the treatment solution mayfurther comprise silver sulfadiazine, preferably in a concentration ofbetween 0.5 and 1 percent (more preferably 0.75 percent). Section 7,below, presents working examples of embodiments set forth in thisparagraph.

In another particular non-limiting embodiment, the present inventionprovides for a hydrophobic polymeric medical article treated by dippingor soaking the article in a treatment solution of hydrophobic polymercomprising chlorhexidine and triclosan, wherein the chlorhexidine andtriclosan are present in amounts such that their combination, in thetreated article, has effective antimicrobial activity. In a specific,non-limiting embodiment, the medical article is a silicone catheter or apolyvinylchloride catheter which has been dipped or soaked in atreatment solution comprising (i) between about 1 and 10 percent, andpreferably about 5 percent, of a silicone polymer; (ii) between 1 and 5percent, and preferably between 1.5 and 2.25 percent, of chlorhexidine;and (iii) between 0.5 and 5 percent, and preferably between 0.5 and 2percent, of triclosan. In related non-limiting embodiments of theinvention, the treatment solution may further comprise silversulfadiazine, preferably in a concentration of between 0.5 and 1 percent(more preferably 0.75 percent). In still other related embodiments, acoating of a hydrophobic polymer may be applied over the treatedarticle. Section 8, below, presents working examples of embodiments setforth in this paragraph.

In another particular non-limiting embodiment, the present inventionprovides for a hydrophobic polymeric medical article treated by dippingor soaking the article in a treatment solution of hydrophilic polymercomprising chlorhexidine and triclosan, wherein the chlorhexidine andtriclosan are present in amounts such that their combination, in thetreated article, has effective antimicrobial activity. In a specific,non-limiting embodiment, the medical article is a silicone catheter orTeflon graft which has been dipped or soaked in a treatment solutioncomprising (i) between about 1 and 10 percent, preferably between about2 and 6 percent, and more preferably about 3 percent, of a biomedicalpolyurethane polymer; (ii) between 1 and 5 percent, and preferablybetween 1.5 and 2.25 percent, of chlorhexidine; and (iii) between 0.5and 5 percent, and preferably between 0.5 and 2 percent, of triclosan.In related non-limiting embodiments of the invention, the treatmentsolution may further comprise silver sulfadiazine, preferably in aconcentration of between 0.5 and 1 percent (more preferably 0.75percent).

Medical articles prepared according to the invention may be treated ontheir external surface, internal surface, or both. For example, and notby way of limitation, where the medical article is a catheter, theinternal surface and/or external surface of the catheter may be treatedaccording to the invention. For example, where it is desired to treatboth internal and external surfaces, an open-ended catheter may beplaced in a treatment solution such that the treatment solution fillsthe catheter lumen. If only the external surface is to come in contactwith treatment solution, the ends of the catheter may be sealed beforeit is placed in the treatment solution. If only the internal surface isto come in contact with treatment solution, the solution may be allowedto pass through and fill the lumen but the catheter is not immersed inthe treatment solution.

Successful treatment of a medical article with a polymer comprising ananti-infective agent may be problematic, particularly where the medicalarticle has a hydrophobic surface. The adherence of the polymer maydepend upon (1) the polymeric matrix in which the anti-infective agentis suspended; (2) compatibility (or lack thereof) between theagent-polymeric matrix and the surface of the article; (3) the solventsystem; and (4) the thickness of polymer/anti-infective agent desirablyapplied. Furthermore, the rates of release of various anti-infectiveagents from diverse polymers may differ. For example, the rate ofrelease of chlorhexidine from a silicone matrix is faster than the rateof release of silver sulfadiazine from the same matrix. In order tocompensate for this difference, one potential solution would be toincrease the amounts of chlorhexidine and silver sulfadiazine in thematrix. Unfortunately, polymers comprising high levels of chlorhexidineand silver sulfadiazine have been found to adhere poorly to siliconecatheters. In order to provide an alternative solution to the problem,two different methods for treating medical articles have been developed:a one-step method, and a two-step method, both of which are set forthbelow.

According to the one-step method of the invention, a polymeric medicalarticle may be treated with a solution comprising one or moreanti-infective agents, and optionally containing a biomedical polymer,dissolved in one or more solvent(s), wherein the solvent(s) selected arecapable of swelling the polymeric medical article to be treated; such asolution is referred to herein as an “impregnating solution”, and theprocess by which the article is treated with anti-infective agent isreferred to as “impregnation”. Suitable solvents include, but are notlimited to, tetrahydrofuran (“THF”), dichloromethane, carbontetrachloride, methanol, ethanol, methyl ethyl ketone, heptane, andhexane, and mixtures thereof. The biomedical polymer may be hydrophilicor hydrophobic, and includes the various polymers set forth above.

If a hydrophilic polymeric medical article is to be impregnated withchlorhexidine and triclosan, the impregnating solution may, in specificnon-limiting embodiments, comprise the following (percentages ofsolvents in this paragraph being volume/volume): (1) 95% ethanol; (2)70% ethanol/30% water; (3) 50% ethanol/50% water; (4) 30% reagentalcohol/70% THF containing 2-3% of a biomedical polyurethane; (5) 90%reagent alcohol/10% THF; or (6) 100% reagent alcohol. Preferred soakingtimes vary between 5 minutes and 1 hour.

In specific, non-limiting embodiments of the invention, a hydrophilicmedical article such as a polyurethane catheter may be impregnated usinga solvent mixture of 70-90% ethanol and 10-30% water and chlorhexidineand triclosan for between 10 and 60 minutes. The article may then bedried for 24-48 hours.

If a hydrophobic polymeric medical article is to be impregnated withchlorhexidine and triclosan, the impregnating solution may, in specificnon-limiting embodiments, comprise the following (percentages ofsolvents in this paragraph being volume/volume): (1) 10% methanol/90%THF; (2) 10% ethanol/90% THF; (3) 30% methanol/70% THF; (4) 30%ethanol/70% THF; (5) 1-5 percent silicone polymer in 10% methanol/90%THF; (6) 1-5 percent silicone polymer in 10% ethanol/90% THF; (7) 1-2percent polylactic acid in 10% methanol/90% THF; (8) 1-2 percentpolylactic acid in 10% ethanol/90% THF; (9) 1-5 percent silicone polymerin 30% methanol/70% THF; (10) 1-5 percent silicone polymer in 30%ethanol/70% THF; (11) 1-2 percent polylactic acid in 30% methanol/70%THF; (12) 1-2 percent polylactic acid in 30% ethanol/70% THF; (13) 1-5percent silicone polymer in 100% methyl ethyl ketone; and (14) 1-2percent polyurethane in 30% ethanol/70% THF. For specific examples, seeSection 15, below.

In specific embodiments, the impregnating solution comprises between 0.2and 10 percent anti-infective agent and between 0.5 and 4 percentbiomedical polymer.

The medical article, or a portion thereof, may be immersed in theimpregnating solution to swell, after which the article may be removedand dried at room temperature until all solvent has evaporated and thearticle is no longer swollen. During the swelling process,anti-infective agent (and small amounts of polymer when present in theimpregnating solution) may be distributed within the polymeric substrateof the article; during drying, the anti-infective agent and biomedicalpolymer (where present) may migrate somewhat toward the surface of thearticle. After drying, the article may be rinsed in either water oralcohol and wiped to remove any excess anti-infective agent and/orpolymer at the surface. This may leave a sufficient amount ofanti-infective agent just below the surface of the article, therebypermitting sustained release of the agent over a prolonged period oftime. Anti-infective agents which may be incorporated by this processinclude but are not limited to chlorhexidine, triclosan, silversulfadiazine, parachlorometaxylene, benzalkonium chloride, bacitracin,polymyxin, miconasole and rifampicin, as well as combinations thereof.

In preferred, non-limiting embodiments of the invention, synergisticcombinations of chlorhexidine and triclosan may be dissolved in amixture of methanol and tetrahydrofuran to produce an impregnatingsolution that may be used to render a silicone catheter anti-infective.

In one specific, non-limiting example, the amount of chlorhexidine maybe between 1 and 5 percent and preferably between 1.5 and 2.25 percentof the impregnating solution, and the amount of triclosan may be between0.5 and 5 percent, and preferably between 0.5 and 2 percent. Theresulting impregnating solution may further contain between 1 and 10percent and preferably between 2 and 4 percent of a biomedical polymersuch as a silicone polymer (e.g., Silastic Type A), polyurethane, orpolycaprolactone. Specific examples of the one-step method are providedin Section 12 below.

According to the two-step method of the invention, the one-step methodmay be used to impregnate a medical article with anti-infective agent,and then the medical article may be dipped into a polymeric solution anddried. This method forms a polymeric coating on the article and furthercontrols the rate of release of anti-infective agent. When the two-stepmethod is practiced, the biomedical polymer may be omitted from thefirst soaking step. Optionally, an anti-infective agent may further becomprised in the polymeric coating. In a specific, non-limiting example,a silicone catheter may be dipped in a mixture of methanol andtetrahydrofuran containing between about 1 and 5 percent, and preferablybetween 1.5 and 2.25 percent, of chlorhexidine; between 0.5 and 5percent and preferably between 0.5 and 2 percent of triclosan; andbetween 1 and 10 percent, and preferably between 2 and 4 percent, of abiomedical polymer (preferably a silicone polymer such as Silastic TypeA) for about 30 minutes, dried, and then dipped in a higherconcentration (but less than 10 percent) of biomedical polymer dissolvedin a suitable solvent. For example, but not by way of limitation, acoating may be applied using a solution of 30% ethanol/70% THFcontaining 2-3 percent of a biomedical polyurethane, or a solution of1-5 percent of Silastic Type A.

Alternatively, a hydrophilic medical article, such as a polyurethanecatheter, may be impregnated with one or more antimicrobial agents andthen coated with a polymer.

Examples of the two-step method are set forth in Sections 8, 16 and 17below.

As set forth in Section 17, below, it has further been discovered thatwhen medical articles were treated with mixtures of chlorhexidine freebase and triclosan, uptake of chlorhexidine and triclosan was enhanced,and the antimicrobial activity of such articles was improved. While notdesiring to be bound to any particular theory, it is believed thatchlorhexidine free base and triclosan form a complex with improvedsolubility. The foregoing effect was observed when chlorhexidine freebase and triclosan were combined in a respective molar ratio of 1:2;according to the invention, chlorhexidine free base and triclosan may bedissolved in a solvent or solvent system at chlorhexidine free base:triclosan molar ratios of 1:1 to 1:3. The total weight percent ofchlorhexidine free base plus triclosan is between 1 and 10 percent. Thechlorhexidine free base and triclosan may be dissolved in a solventsystem comprising water, alcohol, or tetrahydrofuran, and mixturesthereof, to produce an impregnating solution. In one specific,non-limiting example of the invention, a 1:2 ratio of chlorhexidine freebase and triclosan may be dissolved in a solvent system which is 70percent tetrahydrofuran and 30 percent reagent alcohol. A medicalarticle, for example, a polyurethane article, may be impregnated withchlorhexidine free base/triclosan by immersing the article in such animpregnating solution so that the medical article swells without losingsubstantial structural integrity. After impregnation, the article may bedried, and then optionally coated with a polymeric solution, accordingto the two-step method set forth above.

Anti-infective medical articles prepared by other methods (e.g.,extrusion, casting) but being otherwise substantially the same asarticles produced by dipping or soaking, are within the scope of theclaimed invention.

5. EXAMPLE Combinations of Chlorhexidine and Triclosan ExhibitSynergistic Activity in Bacterial Cultures

Various concentrations of chlorhexidine diacetate (“CHA”) and/ortriclosan (“TC”) were dispensed in 1.0 ml trypticase soy broth (“TSB”)containing 20 percent bovine calf serum (“BCS”) and inoculated with 10⁷colony-forming units (“CFU”) of Staphylococcus aureus. After one minute,the cultures were diluted with drug-inactivating medium (1:100 dilutionin LTSB drug inactivating medium, which is 5% Tween 80, 2% lecithin,0.6% sodium oleate, 0.5% sodium thiosulfate, 0.1% protease peptone and0.1% tryptone) and 0.2 ml of the diluted culture was subcultured on atrypticase soy agar plate for the determination of colony counts. Theresults, shown in Table 1, demonstrate the synergistic activity ofcombinations of chlorhexidine and triclosan. For example, whereas 500micrograms per milliliter of CHA causes an approximately 17-folddecrease in CFU, and 500 micrograms per milliliter of triclosan causesan approximately 2400-fold decrease, the combination of these agents isassociated with zero CFU, an at least 1×10⁷-fold decrease.

TABLE I (Anti-infective CFU/ml Agent kill) Concentration (μg/ml) (1minute) CHA 2000 2.1 × 10³ CHA 1000 5.0 × 10⁴ CHA  500 6.0 × 10⁵ TC  5004.2 × 10³ TC  250 2.0 × 10⁵ CHA + TC 2000 + 500 0 CHA + TC 2000 + 250 0CHA + TC 1000 + 250 0 CHA + TC  500 + 500 0 CONTROL 1.0 × 10⁷

6. EXAMPLE Combinations of Chlorhexidine and Triclosan are MoreEffective Than Combinations of Chlorhexidine and Silver SulfadiazineWhen Applied to Hydrophilic Catheters

Polyurethane central venous catheters fabricated Of Tecoflex 93-Apolyurethane were dipped in solutions containing 3 percent of abiomedical poly-urethane (Tecoflex 93-A; “PU”) and CHA, TC and/or silversulfadiazine (“AgSD”) dissolved in 30 percent ethanol and 70 percenttetrahydrofuran (“THF”) (v/v) and air-dried. Bacterial adherence onthese catheters was measured as follows. A 2 cm segment of dippedcatheter was suspended in 3 ml TSB containing 10 percent BCS andincubated in a water bath shaker at 37° C. The media was changed daily.After 2 days the catheter segments were removed and transferred to freshmedia containing 10⁶ CFU/ml of Staphylococcus aureus and incubated for24 hours. The segments were removed, rinsed with saline, and thensuspended in LTSB drug-inactivating medium and sonicated for 20 minutesto remove the adherent bacteria. Aliquots from the LTSB extract werethen subcultured on trypticase soy agar plates to determine colonycounts. The results are presented in Table II, and demonstrate thatcombinations of CHA and TC are superior in preventing bacterialadherence when compared with CHA alone or in combination with AgSD.

TABLE II Adherent Bacteria Coating (CFU/ml) 3% PU + 2.5% CHA 5 × 10⁴ 3%PU + 1.5% CHA + 0.75% AgSD 2 × 10⁴ 3% PU + 1.5% CHA + 1% TC  5 3% PU +1.5% CHA + 0.75% AgSD + 1% TC 40

In additional experiments, additional segments of the same type ofpolyurethane catheters coated with CHA, TC and/or AgSD were tested forthe ability to produce zones of inhibition in trypticase soy agar platesseeded with 0.3 ml of 106 CFU of Staphylococcus aureus, Enterobactercloacae, Candida albicans, and Pseudomonas aeruginosa. The coatedcatheter segments were placed vertically on the seeded plates, whichwere then incubated for 24 hours at 37° C. before the zones ofinhibition were measured. The results, shown in Table III, demonstratethe superior effectiveness of mixtures of chlorhexidine and triclosan.

TABLE III Zone of Inhibition (mm) Coating*: Organism A B C D S. aureus14.5 15.0 13.0 16.5 E. cloacae 9.0 12.0 7.5 3.0 C. albicans 12.0 12.011.5 0 P. aeruginosa 12.5 12.5 12.0 0 *coating A = 3% PU + 2.25% CHAcoating B = 3% PU + 1.75% CHA + 0.5% TC coating C = 3% PU + 1.75% CHA +1.5% AgSD coating D = 3% PU + 0.5% AgSD + 1.75% TC

7. EXAMPLE Hydrophilic Catheters Coated with Hydrophobic PolymerComprising Chlorhexidine and Triclosan Have Antimicrobial Activity

The antimicrobial effectiveness of polyurethane central venous catheters(fabricated from Tecoflex 93-A polyurethane) coated with chlorhexidinediacetate and either triclosan or silver sulfadiazine in two polymericcoatings of differing water absorption were tested. The polymericcoatings, applied as set forth in Section 6 above, comprised eitherpolyurethane 93A (“PU 93A”), a hydrophilic polyurethane having a waterabsorption of about 1-2 percent or polyurethane-siliconeinterpenetrating polymer (“PTUE 205”), a hydrophobicsilicone-polyurethane copolymer having a water absorption of only 0.4%.Antibacterial activity was measured by zones of inhibition, usingmethods as set forth in Section 6, above. The results, as regardsantibacterial activity toward Staphylococcus aureus, Enterobactercloacae, and Candida albicans at days 1 and 3 of culture, are shown inTables IV, V, and VI, respectively, and demonstrate that combinations ofchlorhexidine diacetate and triclosan were effective when comprised inhydrophilic (PU 93A) as well as hydrophobic (PTUE 205) coatings.

TABLE IV Antibacterial Activity Against S. aureus Zone of Inhibition(mm) Coating Day 1 Day 3 3% PTUE 205 + 1.5% CHA + 1.5% TC 16.0 11.0 3%PTUE 205 2% CHA + 0.75% AgSD 14.5 11.0 3% PU 93A + 1.5% CHA + 1.5% TC16.0 11.5 3% PU 93A + 2% CHA + 0.75% AgSD 14.5 11.0

TABLE V Antibacterial Activity Against E. cloacae Zone of Inhibition(mm) Coating Day 1 Day 3 3% PTUE 205 + 1.5% CHA + 1.5% TC 12.0 6.0 3%PTUE 205 2% CHA + 0.75% AgSD 8.5 0 3% PU 93A + 1.5% CHA + 1.5% TC 11.07.0 3% PU 93A + 2% CHA + 0.75% AgSD 7.0 0

TABLE VI Antibacterial Activity Against C. albicans Zone of Inhibition(mm) Coating Day 1 Day 3 3% PTUE 205 + 1.5% CHA + 1.5% TC 11.0 7.0 3%PTUE 205 + 2% CHA + 0.75% AgSD 12.0 9.5 3% PU 93A + 1.5% CHA + 1.5% TC12.5 7.0 3% PU 93A + 2% CHA + 0.75% AgSD 10.0 6.5

8. EXAMPLE Hydrophobic Catheters Treated with Hydrophobic PolymerComprising Chlorhexidine and Triclosan Have Antimicrobial Activity

Silicone central venous catheters fabricated from Dow Corning Q7-4765Asilicone polymer or Q7-4765B silicone polymer were used to determine theeffectiveness of impregnation with hydrophobic polymers comprisingchlorhexidine diacetate and triclosan on hydrophobic substrates. Thesilicone catheters were soaked for about 30 minutes in a solution of 5percent methanol and 95 percent THF (v/v) comprising (i) 2 percentmedical adhesive Silastic Type A and (ii) chlorhexidine diacetate andeither triclosan or silver sulfadiazine. The dipped catheters were driedand then dipped in a solution of 5 percent methanol and 95 percent THF(v/v) containing 5 percent Silastic Type A (“SilA”), and dried again.The catheter segments were then tested for the production of zones ofinhibition on trypticase soy agar plates inoculated with S. aureus or E.cloacae. The results are presented in Table VII.

TABLE VII Zone of Inhibition (mm) Treatment S. aureus E. cloacae 2%SilA + 1.5% CHA + 0.5% TC, then 5% SilA >50 21 2% SilA + 1.5% CHA + 0.5%AgSD, then 5% 17 15 SilA

9. EXAMPLE Triclosan Exhibits Prolonged Release from Polymer Coatings

Silicone central venous catheters fabricated from Dow Corning Q7-4765Asilicone polymer or Q7-4765B silicone polymer were treated as set forthin Section 8, above, and then, immediately after drying, were extractedin dichloromethane/methanol/water (50%/25%/25%, v/v) in order todetermine the amount of agent contained in the catheter segment tested(i.e., the uptake). To determine the rate of drug release, cathetersegments were suspended in saline and incubated at 37° C. for up toseven days; the saline was collected and replaced with fresh saline onthe first day and every 48 hours thereafter, and the amount of drugpresent in the collected saline was measured. The results are presentedin Table VIII.

TABLE VIII Uptake Release (μg/cm) Treatment (μg/cm) Day 1 Day 3 Day 5Day 7 2% SilA + 2% CHA, 60 28.0 4.1 3.1 2.6 then 5% SilA 2% SilA + 2%TC, then 1168 10.0 9.5 11.1 11.4 5% SilA

Silicone catheters impregnated with Silastic Type A comprising either 2%triclosan or 2% chlorhexidine diacetate were then tested for the abilityto produce zones of inhibition on trypticase soy agar plates inoculatedwith S. aureus, E. cloacae, C. albicans, or P. aeruginosa. The resultsof these experiments are shown in Table IX, and demonstrate that whenhigher concentrations of triclosan or chlorhexidine diacetate alone wereused, triclosan-treated catheters were found to be equally or moreeffective than CHA-treated catheters.

TABLE IX Zones of Inhibition (mm) 2% SilA + 2% CHA, 2% SilA + 2% TC,Treatments: then 5% SilA then 5% SilA Organism Day 1 Day 3 Day 1 Day 3S. aureus 17.5 16.0 >50 >50 E. cloacae 15.0 9.0 40.0 40.0 C. albicans13.5 6.0 13.0 13.0 P. aeruginosa 13.0 0 8.5 0

10. EXAMPLE Uptake of Chlorhexidine and Triclosan in Ptfe Grafts

Arterial grafts fabricated from polytetrafluoroethylene (“PTFE”) werecut into segments and impregnated with Silastic Type A comprisingchlorhexidine diacetate or triclosan in 30% methanol/70% THF (v/v), inproportions set forth below. The treated grafts were then extracted withdichloromethane/methanol/water (50%/25%/25%, v/v), and the amounts ofsolubilized anti-infective agents were determined. Table X shows theuptake of agent by the treated grafts.

TABLE X Treatment Agent Uptake (μg/cm) 2% SilA + 2% CHA  895 2% SilA +2% TC 2435

11. EXAMPLE Antimicrobial Effectiveness of Medical Articles Fabricatedfrom Teflon, Dacron or Natural Rubber Latex and Impregnated withCombinations of Chlorhexidine and Triclosan

Chlorhexidine diacetate and either triclosan or silver sulfadiazine, inproportions set forth below, were dissolved in 5% methanol/95% THF(v/v). Segments of Dacron grafts, PTFE grafts, and natural rubber latexurinary catheters were then soaked in the resulting solutions for 15minutes to impregnate the segments with anti-infective agents. Thisprocedure allows the polymer substrates of the devices to incorporateanti-infective agent. The segments were then removed from the soakingsolution, dried, rinsed with water, and wiped. The ability of thetreated segments to produce zones of inhibition on trypticase soy agarplates inoculated with S. aureus and E. cloacae was then tested. Theresults, shown in Tables XI-XIII, demonstrate that the combination ofchlorhexidine and triclosan produced superior antimicrobial resultscompared to the combination of chlorhexidine and silver sulfadiazine.

TABLE XI PTFE Graft Zone of Inhibition (mm) Impregnating Solution S.aureus E. cloacae 5% CHA + 0.5% TC 37.0 22.0 1.5 CHA + 0.75% AgSD 22.016.5

TABLE XII Dacron Graft Zone of Inhibition (mm) Impregnating Solution S.aureus E. cloacae 5% CHA + 0.5% TC >40 30.0 1.5 CHA + 0.75% AgSD 26.027.0

TABLE XIII Latex Catheter Zone of Inhibition (mm) Impregnating SolutionS. aureus E. cloacae 5% CHA + 0.5% TC 26.0 20.0 1.5 CHA + 0.75% AgSD18.0 12.0

12. EXAMPLE Antimicrobial Effectiveness of Silicone Catheters Preparedby a One-Step Impregnation Method

Silicone catheters, as used in Example 8, were prepared by a one-stepimpregnation method as follows. Segments of the silicone catheters weresoaked for about 30 minutes in impregnating solutions of 90% THF/10%methanol (v/v) containing 2% Silastic Type A, chlorhexidine, and eithersilver sulfadiazine or triclosan. The segments were then dried, andtested for their ability to produce zones of inhibition (at one andthree days) in trypticase soy agar plates inoculated with S. aureus, E.cloacae, C. albicans, and P. aeruginosa. The results, presented in TableXIV, demonstrate the effectiveness of chlorhexidine andtriclosan-impregnated catheters.

TABLE XIV Zones of Inhibition (mm) 2% SilA + 2% SilA + 1.5% CHA, + 1.5%CHA, + Treatments: 0.5% TC 0.5% AgSD Organism Day 1 Day 3 Day 1 Day 3 S.aureus >40 39 17.5 13.5 E. cloacae 21 21 15 8 C. albicans 13.5 7 13.5 6P. aeruginosa 13.5 6.5 13 0

Additional formulations of impregnating solutions were tested for theirability to render the same type of silicone catheter segmentsanti-infective against C. albicans, the microorganism which appeared tobe inhibited only by relatively high amounts of anti-infective agent.The following impregnating solutions comprised chlorhexidine, triclosanand either Silastic Type A, polycaprolactone, or no polymer in a 5%methanol/95% THF solvent. Table XV shows that when both polymer andanti-infective agent were comprised in the impregnating solution, higheranti-infective activity was achieved.

TABLE XV Impregnating Solution Zone of Inhibition (mm) 4% SilA + 5%CHA + 1% TC 12.0 1% polycaprolactone + 5% CHA + 1% TC 12.0 No polymer,5% CHA + 1% TC 6.5

13. EXAMPLE Diffusion of Anti-Infective Agents from Medical ArticlesTreated with Impregnating solutions with and Without Polymer

The following impregnating solutions, “A” and “B”, were used toimpregnate segments of Dacron and PTFE grafts. The treated grafts werethen rinsed with saline, and the amounts of anti-infective agentincorporated into the grafts were determined, before and after rinsing,by extraction of anti-infective agent withdichloromethane/methanol/water (50%/25%/25%, v/v). The results, setforth in Table XVI, demonstrate that the addition of a polymer to theimpregnating solution produces a treated medical article which exhibitsgreater retention of anti-infective agent.

TABLE XVI Drug Levels (μg/cm) Dacron Graft PTFE Graft Solution: A B A BSolution A Before rinsing 392 548 73 90 After rinsing 353 547 56 88Solution B Before Rinsing 409 573 50 44 After Rinsing 132 553 24 44Solution A: 1% polycaprolactone + 0.1% CHA + 0.02% TC, in 5%methanol/95% THF (v/v) Solution B: 0.1% CHA + 0.02% TC, in 5%methanol/95% THF (v/v)

14. EXAMPLE Drug Uptake and Release by Hydrophilic Catheters Impregnatedwith Chlorhexidine or Triclosan

Polyurethane central venous catheter segments fabricated of Tecoflex93-A polyurethane were impregnated with solutions “C”, “D”, “E”, “F” and“G” set forth below by soaking the catheter segments for about twominutes followed by drying and rinsing with water. Drug uptake wasmeasured by extracting the impregnated catheter segments withdichloromethane/methanol/water (50%/25%/25% v/v). Drug release wasmeasured over a period of six days by suspending the catheter segmentsin saline (one 2 cm segment in 2 ml saline), and agitated in a heatedwater bath at 37° C.; the saline was changed daily and drug release wasmeasured as described above. The results are shown in Table XVII.Polyurethane, as set forth below, is Tecoflex 93-A polyurethane.

TABLE XVII Drug Release (μg/cm) Uptake Day No. Solution Drug (μg/cm) 1 23 4 5 6 C CHA 197 78 36 20 2.6 0.8 0.8 D TC 300 0.4 .13 0.1 0.1 0.1 0.1E CHA 202 66 16.8 7.0 5.0 5.0 5.0 TC 230 0.4 0.3 <.1 <.1 <.1 <.1 F CHA254 15 9.6 7.8 2.5 2.5 2.5 G CHA 223 7.1 3.5 3.0 0.8 0.8 0.8 TC 368 <.1<.1 <.1 <.1 <.1 <.1 Solution C: 3% polyurethane + 3% CHA in 30% reagentalcohol/70% THF Solution D: 3% polyurethane + 3% TC in 30% reagentalcohol/70% THF Solution E: 3% polyurethane + 2% CHA + 2% TC, in 30%reagent alcohol/70% THF Solution F: 2% CHA in 95% ethanol Solution G: 3%CHA + 1% TC in 95% ethanol

15. EXAMPLE Release of Chlorhexidine and Triclosan from ImpregnatedSilicone Catheter Segments

Segments of silicone central venous catheters fabricated from DowCorning Q7-4765A silicone polymer or Q7-4765B silicone polymer wereimpregnated with either solution H or I by soaking for 30 minutes, andthen the release of drug was measured daily by methods set forth above.The results of these measurements are presented in Table XVIII.

TABLE XVIII Daily Release (μg/cm) Solution Drug Day 1 Day 2 Day 3 Day 4Day 5 H CHA 2.7 1.0 0.6 0.9 0.9 I CHA 0.8 0.9 0.6 0.8 0.8 TC 2.6 5.6 2.31.5 1.5 Solution H: 2% SilA + 5% CHA in 10% methanol/90% THF (v/v)Solution I: 2% SilA + 5% CHA + 2% TC in 10% methanol/90% THF (v/v)

16. Method of Rendering Polyurethane Catheters Infection-Resistant byImpregnation with a Synergistic Combination of Chlorhexidine andTriclosan

A one-step method (“Method 1”) and a two-step method (“Method 2”) wereused to treat polyurethane catheters.

Method 1: An entire polyurethane central venous catheter assemblyincluding the hub, extension line and catheter body may be soaked in analcoholic solution containing chlorhexidine and triclosan for a specifictime period sufficient to impregnate these elements with chlorhexidineand triclosan without altering the integrity of the polyurethanesubstrate. The following solvent systems and soaking times are suitable.The concentrations of chlorhexidine and triclosan range from 0.5-5%.

TABLE XIX Solvent system Soaking time  95% ethanol/5% water  2-30minutes 100% reagent alcohol  2-30 minutes  90% reagent alcohol/10%water  5-60 minutes  80% reagent alcohol/20% water  5-60 minutes  70%reagent alcohol/30% water 10-60 minutes  90% ethanol/10% water  5-60minutes  80% ethanol/20% water  5-60 minutes  70% ethanol/30% water10-60 minutes  20% methanol/10% isopropanol/ 10-60 minutes  40% reagentalcohol/  30% water

Selection of the solvent mixture depends on the type of polyurethanesubstrate and antimicrobials used for impregnation. After soaking, thecatheter is rinsed in water for 24 to 48 hours to allow the catheter toregain its original integrity and size.

Method 2. A catheter impregnated with chlorhexidine and triclosanaccording to Method 1 is then dipped in 70% THF/30% reagent alcohol/1-3%polyurethane/1-3% chlorhexidine/1-3% triclosan.

Catheters prepared by Method 1 provide a relatively slow and steadyrelease rate from the luminal surface and outer surface for a prolongedperiod of time. This pattern of drug release results from the relativelylower ratio of drug to polyurethane matrix (0.015).

Catheters prepared by Method 2 exhibit biphasic drug release. The higherratio of drug to polyurethane in the outer coating (1.3) permits aninitial release of large amounts of drugs (which may inactivate bacteriaentering through the skin at the time of insertion) followed by slow andsteady release of drug impregnated in the catheter by Method 1. Theouter polyurethane coating acts as a barrier and permits the controlledrelease of drug over a prolonged period of time.

As specific examples, Tecoflex polyurethane catheters were preparedusing the following method and then tested for antimicrobial efficacy intheir luminal and outer surfaces:

i) catheters were soaked in 2% chlorhexidine dissolved in 100% reagentgrade alcohol for 1 hour, rinsed in water, and dried for 24-48 hours(“Catheter C”);

ii) catheters were soaked in 2% chlorhexidine+2% triclosan dissolved in100% reagent grade alcohol for 15 minutes, rinsed in water, and driedfor 24-48 hours (“Catheter TC”);

iii) catheters were soaked in 2% triclosan in 70% reagent alcohol/30%water for 2 minutes, rinsed in water, and dried for 24-48 hours(“Catheter T”);

iv) catheter C (above) was dipped in 3% polyurethane+2% chlorhexidinedissolved in 70% THF/30% reagent alcohol (“Catheter C-C”);

v) catheter C (above) was dipped in 3% polyurethane+2%chlorhexidine+0.75% AgSD dissolved in 70% THF/30% reagent alcohol(“Catheter C-A”);

vi) catheter T (above) was dipped in 2% chlorhexidine+2% triclosandissolved in 70% THF/30% reagent alcohol (“Catheter T-R”);

vii) catheter TC (above) was dipped in 2% chlorhexidine+2% triclosandissolved in 70% THF/30% reagent alcohol (“Catheter TC-R”); and

viii) catheter TC (above) was dipped in 2% chlorhexidine+0.75% AgSDdissolved in 70% THF/30% reagent alcohol.

Trypticase soy agar plates were seeded with 10 CFU Staphylococcusaureus/ml and 0.5 cm segments of catheter were embedded vertically. Theplates were then incubated for 24 hours at 37° C. and zones ofinhibition were measured. The results are shown in Table XX.

TABLE XX Catheter type (mm) Zone of Inhibition Surface Lumen Outer C 1515 T 21 21 TC 25 25 C-C 15 18 C-A 15 18 T-R 21 25 TC-R 23 26 TC-A 23 26

17. Method of Rendering Polyurethane Catheters Infection-Resistant byImpregnation with a Synergistic Combination of Chlorhexidine Free Baseand Triclosan

It was further discovered that when catheters were coated usinginsoluble chlorhexidine free base and triclosan, a solublechlorhexidine/triclosan complex was formed which improved the druguptake and, therefore, the efficacy of the catheter.

Method 3: Catheters prepared by Method 1 (see Section 16) were dried for24-72 hours and then their outer surfaces were dipped in a polyurethanesolution (1-3% polyurethane dissolved in THF/alcohol). Cathetersprepared by this method exhibited a large amount of drug releaseinitially followed by a small but synergistically effective amount ofdrug release for a prolonged period of time.

Method 4: Followed the same procedure as Method 1, except that insolublechlorhexidine free base (CHX) was solubilized with triclosan (1 molarCHX:2 molar triclosan ratio), which forms a complex with CHX. Aftersoaking for 5-10 minutes the catheters were dried for 1-3 days and thenthe outer surface was dipped in either a polyurethane solution alone(1-3% polyurethane) or a solution of polyurethane containing CHX andtriclosan (TC).

When relatively soluble chlorhexidine salts such as chlorhexidineacetate (CHA) were used to impregnate catheters, the release wasundesirably rapid. We investigated the use of CHX as a substitute forCHA. CHX is not soluble is water or alcohol but, surprisingly, we foundthat when it was combined in a 1:2 molar ratio with triclosan, analcohol soluble complex formed.

The uptake of chlorhexidine from a solution containing CHX-TC complexwas greater than that obtained from a CHA-TC solution despite a higherCHA concentration in the soaking solution. Due to higher chlorhexidinelevels and higher rate of chlorhexidine release from the substrateresulting from impregnation with CHX-TC complex, the infectionresistance of the catheters was greater than those containing only CHA.

Method 5: Same as method 4 but the soaking and outer coating solutionsalso contained soluble chlorhexidine acetate.

As specific examples, the following experiments were performed usingTecoflex catheters:

(1) Catheters were prepared according to Method 3. Specifically,catheters were soaked in 5% CHA+1% TC dissolved in reagent alcohol for10 minutes, dried for three days, and then the outer surface was dippedin 2.7% Tecoflex polyurethane dissolved in THF/reagent alcohol(70%/30%); the resulting catheters are referred to as type 1, and thepolyurethane/THF/reagent alcohol solution is referred to as Solution J.

(2) A second group of catheters was prepared as in (1), but instead ofusing Solution J for the outer coating, another solution was used: 0.5%CHX+0.5% TC+2.7% polyurethane dissolved in 70% THF/30% reagent alcohol(“Solution K”). The resulting catheters are referred to as type 2.

(3) Catheters were prepared using Method 5. Specifically, catheters weresoaked in a solution containing 2% CHX+2% CHA+2% TC dissolved in reagentalcohol for 10 minutes, dried for 3 days and their outer surfaces weredipped in Solution J. The resulting catheters are referred to as type 3.

(4) Catheters were prepared as in (3) but were dipped in Solution K toproduce an outer coating. The resulting catheters are referred to astype 4.

(5) Catheters were prepared according to Method 4. Specifically,catheters were soaked for 10 minutes in 3% CHX+3% TC in reagent alcohol,dried for 3 days, and outer surface coated in Solution J. The, resultingcatheters are referred to as type 5.

(6) Catheters were prepared as in (5) but outer surface coated withSolution K. The resulting catheters are referred to as type 6.

(7) Catheters were prepared according to Method 3. Specifically,catheters were soaked in a solution containing 5% CHA+1% TC in reagentalcohol for 10 minutes, dried for 3 days and then outer surface coatedusing Solution J. The resulting catheters are referred to as type 7.

(8) Catheters were prepared as in (7), except were outer surface coatedwith 2.7% polyurethane+3% CHA in 70% THF/30% reagent alcohol. Theresulting catheters are referred to as type 8.

Segments of catheter types 1-8 were placed vertically in inoculatedtrypticase soy agar plates inoculated with 108 CFU of Staphylococcusaureus per plate, and incubated for 24 hours. After measuring the zonesof inhibition, the catheters were transferred daily to fresh cultureplates (shown in Table XXI).

TABLE XXI Catheter type (mm) Day Zone of Inhibition 1 21 12.0 2 21 13.03 21 17.0 4 21 20.0 5 21 20.0 6 21 23.0 7 21 5.0 8 21 9.0

The amount of drug uptake per cm/catheter in catheters prepared usingvarious soaking solutions was measured as set forth above.

TABLE XXII Drug Uptake/cm catheter Soaking Solution ChlorhexidineTriclosan 5% CHA 260-310 — 5% CHA + 2% TC 280-300 450-480 2% CHX + 2%TC + 2% CHA 480-520 300-370 3% CHX + 3% TC 550-660 600-700

The luminal adherence of bacteria was quantified in cathetersimpregnated with antimicrobials and then coated with a solution of 2.7percent Tecoflex 93A and various antimicrobial agents. Bacterialadherence was measured as follows. 12 cm segments of test and control7Fr catheters were each connected to an individual channel of aperistaltic pump via an extension line, hub, and injection cap. The hubswere inoculated initially and after 24 hours with 10⁶ cfu of S. aureuswhich causes the extension line to become colonized thus acting as acontinuous source of bacteria for seeding lumens. The lumens werecontinuously perfused at a rate of 20 ml/hour with trypticase soy broth(TSB) diluted 1:10 with physiological saline over the course of 7 days.At the end of one week the catheter segments were disconnected and theirouter surfaces disinfected with 70% ethanol. Each lumen was flushed withsterile TSB to remove non-adherent bacteria. Each catheter was then cutinto 2 cm segments each of which is further divided into 2 mmsubsegments and placed in tubes containing 4 ml of antisepticinactivating broth (LTSB). The tubes were sonicated for 20 minutes at 4°C. to remove bacteria adhering to the lumens. To quantify the adherence,a 0.5 ml aliquot of the LTSB extract was subcultured on trypticase soyagar plates. The results are shown in Table XXIII.

TABLE XXIII DRUG IN BACTERIAL SOAKING SOLUTION DRUG IN ADHERENCE(cfu/cm) OUTER COATING IN LUMEN 5% CHA 3% CHA 3 × 10⁴ 5% CHA + 0.5% TC2% CHA + 2% TC 3 × 10² 2% CHX + 2% CHA + 2% CHA + 2% TC 0 2% TC 3% CHX +3% TC 0.5% CHX + 0.5% TC 0 0 (control) 0 4 × 10⁶ 2% CHX + 2% CHA + noouter coating 5 2% TC

Various publications are cited herein, which are hereby incorporated byreference in their entireties.

1. A medical article wherein the internal surface of the article hasbeen impregnated with a treatment solution comprising chlorhexidine, andwherein the chlorhexidine consists essentially of a mixture ofchlorhexidine free base and a chlorhexidine salt.
 2. The article ofclaim 1 wherein the treatment solution comprises between about one tofive percent chlorhexidine.
 3. The article of claim 1 further comprisingsilver sulfadiazine.
 4. The article of claim 1 wherein the treatmentsolution further comprises a polymer.
 5. The article of claim 4 whereinthe treatment solution comprises between about one to ten percent of thepolymer.
 6. The article of claim 4 wherein the polymer is hydrophobic.7. The article of claim 6 wherein the hydrophobic polymer is selectedfrom the group consisting of polytetrafluoroethylene, DACRON, polyesterfabric, polyvinylchloride, polyurethane, biomedical silicone polymer,and silicon-polyurethane copolymer.
 8. The article of claim 4 whereinthe polymer is hydrophilic.
 9. The article of claim 8 wherein thehydrophilic polymer is selected from the group consisting of naturalrubber latex and biomedical polyurethane.
 10. The article of claim 1wherein the external surface of the article has been impregnated with atreatment solution comprising chlorhexidine, and wherein thechlorhexidine consists essentially of a mixture of chlorhexidine freebase and a chlorhexidine salt.
 11. The article of claim 1 wherein thearticle is a catheter.
 12. A method of preparing a medical article, themethod comprising: (i) contacting the internal surface of the articlewith an impregnating solution comprising a solvent and chlorhexidine,and (ii) soaking the article in the solution for a period of timesufficient to allow the article to swell; wherein the solvent isselected from the group consisting of water, reagent alcohol,tetrahydrofuran, and mixtures thereof; and and wherein the chlorhexidineconsists essentially of a mixture of chlorhexidine free base and achlorhexidine salt.
 13. The method of claim 12 wherein the total weightof chlorhexidine is between about one and ten percent of the weight ofthe solution.
 14. The method of claim 12 further comprising removing thearticle from the solution and drying the article.
 15. The method ofclaim 12 further comprising contacting the article with a secondsolution, wherein the second solution comprises a polymer.
 16. A methodof preparing a medical article, the method comprising: (i) contactingthe internal surface of the article with an impregnating solutioncomprising a solvent, chlorhexidine free base and chlorhexidine salt,and (ii) soaking the article in the solution for a period of timesufficient to allow the article to swell; wherein the solvent isselected from the group consisting of water, reagent alcohol,tetrahydrofuran, and mixtures thereof.
 17. The method of claim 16wherein the total weight of chlorhexidine is between about one and tenpercent of the weight of the solution.
 18. The method of claim 16further comprising removing the article from the solution and drying thearticle.
 19. The method of claim 16 further comprising contacting thearticle with a second solution, wherein the second solution comprises apolymer.